tbuckley/cabot-search huggingface dataset:
Abstract 2740: Stochastic modeling uncovers the interplay between early cancer progression and adaptive immune-specific cancer escape
Authors: Jason T. George
Journal: Cancer Research (2022)

Abstract The lack of durable therapeutic interventions continues to limit cancer treatment efficacy. While breakthroughs in immunotherapy have improved patient survival for some disease subtypes, immune escape is an unfortunate and common hallmark of cancer evasion. Understanding the dynamic interplay between an evolving and heterogeneous malignant population and the adaptive immune system, consisting of millions of unique T cells, is therefore required for designing optimized treatment strategies. We begin by describing the implications of cancer escape via durable evasion events, such as major histocompatibility antigen presentation down-regulation. Durable escape is then applied to relate observed cancer age-specific incidence to physiologic impairments in T cell turnover and diversity. We then discuss a more generalized stochastic process that enables transient escape and recurrent recognition via distinct T cell subclones. This co-evolutionary model predicts repeated immune recognition and cancer evasion prior to disease manifestation. Using this model, we find that T cell turnover and cancer mutation rates explain differences in early age incidence data across nearly all cancer types. Lastly, we introduce a modeling approach for understanding the extent of optimality occurring in cancer evasion via tumor-associated antigen downregulation, emphasizing the utility of foundational modeling frameworks for optimizing cancer T cell immunotherapy. Citation Format: Jason T. George. Stochastic modeling uncovers the interplay between early cancer progression and adaptive immune-specific cancer escape [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2740.
New Federal Agency for Biomedical and Health Research
Authors: Melissa Suran
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract 2499: Identifying DNA methylation signatures of retinoblastoma via aqueous humor, a novel ocular liquid biopsy
Authors: Liya Xu, Hongtao Li, Dan Weisenberger, Gangning Liang, Jesse Berry
Journal: Cancer Research (2022)

Abstract Introduction: Retinoblastoma (Rb) is the most common childhood intraocular cancer. Tissue biopsy of Rb can cause tumor spread, so it is contraindicated. We demonstrated that aqueous humor (AH), an ocular fluid, is a high yield liquid biopsy enabling in vivo detection of tumor-derived cell free DNA (cfDNA) thus overcoming the contraindication to biopsy. Prognostic genomic cfDNA biomarkers in Rb AH enables objective real time disease monitoring. In ~13% of Rb, tumor progression is driven by epigenetic deregulation of tumor-promoting pathways without detectable genomic alterations. However, epigenetic studies have been done only on tumor from surgically removed eyes. The frequency and effect of epigenomic regulation in eyes that have been saved with therapy is not clear due to no access to in vivo tumor. Therefore, epigenetic analysis of AH cfDNA is highly desired to understand the broader spectrum of Rb tumorigenesis and prognosis. Materials and Methods: 16 AH samples and 4 Rb tumors from 12 patients with 14 Rb eyes were included in the study. We conducted global DNA methylation profiling of tumor tissues from surgically removed Rb eyes, AH samples collected from different clinical stages with different treatment outcomes using the Illumina Infinium EPIC DNA methylation BeadArray platform. Publicly available DNA methylation data of normal retina, Rb eyes, and Rb patients were obtained from Gene Expression Omnibus (GEO, GSE57362) for cell type DNA methylation comparisons. Results: Our preliminary studies revealed a high degree of concordance in genome-wide differential DNA methylation patterns between paired AH and tumor samples. Integrating our data with large public datasets, we identified reliable RB DNA methylation signatures in cfDNA that have potential diagnostic and prognostic values. We also identified hypermethylation at RB1 promoter, which suggested RB1 is druggable to DNA methylation inhibitors. By integrating DNA methylation data with gene expression data, we identified over 300 differentially expressed genes potentially regulated by DNA methylation change. Pathway analysis indicated several tumor suppressor pathways (e.g., RB1 and P53 pathways) were suppressed and some oncogenic pathways were activated (e.g., E2F pathways). Conclusions: Our study sets the stage for exploiting epigenetic markers in AH and identifying potential therapeutic targets to improve the clinical management of patients with RB. Citation Format: Liya Xu, Hongtao Li, Dan Weisenberger, Gangning Liang, Jesse Berry. Identifying DNA methylation signatures of retinoblastoma via aqueous humor, a novel ocular liquid biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2499.
Abstract 5809: eIF2α O-GlcNAcylation promotes oxidative stress in arginine-starved triple-negative breast cancer cells
Authors: Yu-Wen Hung, Yi-Chang Wang, David K. Ann
Journal: Cancer Research (2022)

Abstract Redox balance is the critical liaison for cancer homeostasis. Moderate increases in reactive oxygen species (ROS) levels can lead to cancer formation and progression. However, a disproportional increase of ROS levels changes equilibrium in cell redox status and leads to cancer cell death. Therefore, exogenous agents or antioxidant inhibitors which augment ROS generation become a potential new way to target cancer cells. We have found excessive accumulation of cellular proteins during arginine starvation causes stresses on the endoplasmic reticulum (ER) protein folding machinery resulting in elevated ROS levels. In this study, we continue to examine that arginine starvation-attenuated heme oxygenase-1 (HO-1) translation exacerbates the high ROS level to kill the cancer cells. In addition, HO-1 translational downregulation is due to arginine starvation-induced O-GlcNAcylation of eIF2α at S219, T239, and T241 residues. Loss of O-GlcNAcylation at eIF2α significantly rescues arginine starvation-reduced HO-1 protein level, resulting in better recovery and migratory properties from starvation and lower ROS level. In addition, arginine starvation-induced O-GlcNAcylation of eIF2α to suppress HO-1 translation is independent of its phosphorylation at S51, which is another stress-stimuli modification that regulates eIF2 involved protein translation. Arginine starvation exploits O-GlcNAcylation to antagonize eIF2α phosphorylation-induced HO-1 expression. Taken together, arginine starvation is a potential anti-cancer therapy in which induced eIF2α O-GlcNAcylation presents itself as a critical role for metabolic adaptation and tumor growth by dysregulating the antioxidant protein in cancer cells. Citation Format: Yu-Wen Hung, Yi-Chang Wang, David K. Ann. eIF2α O-GlcNAcylation promotes oxidative stress in arginine-starved triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5809.
Abstract 1808: Impact of nanoengineering on redox regulation and CXCR4-mediated homing of mesenchymal stem cells
Authors: Drishti Sehgal, Susheel Kumar Nethi, Carmen Merali, Salim Merali, Jayanth Panyam, Swayam Prabha
Journal: Cancer Research (2022)

Abstract Mesenchymal stem cells (MSCs) are being investigated for several therapeutic applications, including cancer, inflammation, tissue repair, and transplantation because of their ability to home to injured and inflamed tissues. Despite the large number of preclinical studies investigating engineered MSCs as therapeutic agents and numerous clinical trials investigating MSCs for other therapeutic applications, there have only been a handful of clinical trials investigating MSCs for treating solid tumors, and none have progressed beyond Phase I/II. Inefficient tumor homing ability and a lack of understanding of fundamental mechanisms may contribute to the limited translational success of MSC-based therapies. We hypothesized that nanoengineering MSCs with anticancer drugs induces oxidative stress, and MSCs counteract this stress by activating Nrf2, which increases the expression of various antioxidant proteins, including CXCR4, a key mediator of MSC tumor homing. We performed global label-free, unbiased proteomics on nanoengineered MSCs using modified in-Stage technology. Our studies indicated that MSCs nanoengineered with paclitaxel underwent significant changes in the overall proteome compared to either untreated MSCs or MSCs loaded with blank nanoparticles. Analysis of molecular function profile revealed that loading paclitaxel in MSCs significantly enhanced the expression of proteins involved in the antioxidant and catalytic activity and protein binding. The biological process profile also showed a similar increase in defense response and an increase in metabolic processes. It was further found that MSCs nanoengineered with PTX lead to significant upregulation of nrf2, the master regulator of antioxidant responses, and CXCR4, a direct target of Nrf2 and a key mediator of tumor homing. Also, an increase in CXCR4 expression was directly proportional to paclitaxel loading in cells. These studies suggest nanoengineering of MSCs impacts their biology, which likely contributes to their improved tumor homing capacity in vivo. Citation Format: Drishti Sehgal, Susheel Kumar Nethi, Carmen Merali, Salim Merali, Jayanth Panyam, Swayam Prabha. Impact of nanoengineering on redox regulation and CXCR4-mediated homing of mesenchymal stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1808.
Abstract LB151: Deep learning - based protein therapeutics design to treat HER2+ cancers
Authors: Ziwei Liang, Tom Murray, Max Bluestone, Chris Zoumadakis, Luke Martin, Alexey Vlasenko, Jeffrey LaFrence, John Lazar, Matthias Denecke, David Longo
Journal: Cancer Research (2022)

Abstract Background: HER2 amplification and activation occurs in approximately 15~25% of all breast cancers and is further indicated in other cancer types with high un-met medical needs, such as cholangiocarcinoma, ovarian and esophageal cancer. Further improvement of current HER2 targeting therapeutics on safety and efficacy remains to be desired. Deep learning - based computational approach, such as AlphaFold, has been successfully applied to the understanding of protein structure. However, its applications to protein therapeutic design remain largely underdeveloped. Method: We have developed an end-to-end protein design engine Apollo, which can be used to design target-binding protein therapeutics in silico. Apollo uses recurrent neural networks (RNNs), transformers and graph convolution neural networks (GCNs) to represent proteins, protein structures and protein-protein interactions. This is further improved by multi-head and hierarchical attention layers. Using generative AI, Apollo can either generate putative binding proteins de novo, or to optimize protein lead molecules. Candidate proteins are evaluated in silico for binding affinity and specificity, secondary and tertiary structure, isoelectric point, solubility, and other drug-like properties. Generated designs are iteratively improved by Apollo via a reinforcement learning loop. Results: Apollo has achieved high prediction accuracy by in silico evaluations, using metrics such as AUC and the confusion matrices. Using Apollo, we then designed mini protein binders of 50~100 aa to target HER2 extracellular domain (ECD). These binders can be produced with high yield and purity using mammalian protein expression systems. From de novo generation, the designed candidates are shown to bind to human HER2 with EC50 in the nanomolar range by ELISA. From optimizations based on lead molecules, the designed candidates have shown improved production yield and thermostability while maintaining binding affinity. Conclusions: We have shown the proof-of-concept success of using machine learning to design protein therapeutics. Citation Format: Ziwei Liang, Tom Murray, Max Bluestone, Chris Zoumadakis, Luke Martin, Alexey Vlasenko, Jeffrey LaFrence, John Lazar, Matthias Denecke, David Longo. Deep learning - based protein therapeutics design to treat HER2+ cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB151.
Abstract 4148: Non-redundant upregulation of CD112R (PVRIG) and PD-1 on cytotoxic T-lymphocytes located in T-cell-nests of colorectal cancer
Authors: Maximilian Lennartz, Cheng Yang, Tim Mandelkow, Elena Bady, Ronald Simon, Claudia Hube-Magg, Guido Sauter, Niclas C. Blessin
Journal: Cancer Research (2022)

Abstract Focal T-lymphocyte aggregates occur commonly in colorectal cancer, but their biological significance is unknown. To study focal aggregates of T-lymphocytes, a deep learning-based framework for automated identification of T-cell accumulations (T-cell-nests) was developed using CD8, PD-1, CD112R, and Ki67 multiplex fluorescence immunohistochemistry. To evaluate the clinical significance of these parameters, a cohort of 523 colorectal cancers with clinical-follow up data was analyzed. The spatial analysis of locally enriched CD8+ T-cell densities and cell-to-cell contacts identified T-cell-nests in the tumor microenvironment of colorectal cancer. CD112R and PD-1 expression on CD8+ T-cells located in T-cell-nests was found elevated as compared to CD8+ T-cells in all other tumor compartments (p&amp;lt;0.001 each). Although the highest mean CD112R expression on CD8+ T-cells was observed at the invasive margin, the PD-1 expression on CD8+ T-cells was elevated in the center of the tumor (p&amp;lt;0.001 each). Across all tissue compartments, proliferating CD8+ T-cells showed higher relative CD112R and PD-1 expression compared to non-proliferating CD8+ T-cells (p&amp;lt;0.001 each). Integration of all available spatial and immune checkpoint expression parameters (AUC: 0.65) revealed a superior predictive performance for overall survival compared to the commonly used CD8+ TILs density (AUC 0.57, p&amp;lt;0.001). Cytotoxic T-cells with elevated CD112R and PD-1 expression levels are orchestrated in T-cells-nests of colorectal cancer, predict favorable patient’s outcome and the spatial non-redundancy underlies fundamental differences of both inhibitory immune checkpoints that provide a rationale for dual anti-CD112R/PD-1 immune checkpoint therapy. Citation Format: Maximilian Lennartz, Cheng Yang, Tim Mandelkow, Elena Bady, Ronald Simon, Claudia Hube-Magg, Guido Sauter, Niclas C. Blessin. Non-redundant upregulation of CD112R (PVRIG) and PD-1 on cytotoxic T-lymphocytes located in T-cell-nests of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4148.
Abstract 5074: Investigating the cellular uptake of liposomal delivery system using cellular models of lymphoma
Authors: Joyce Edlyne Chima Bom, Tien Van Le, Tracy Togba-Bass, Erica Kim, Robert Campbell
Journal: Cancer Research (2022)

Abstract Background: Lymphoma accounts for more than 4% of cancer diagnoses in the United States. Conventional treatment strategies for lymphoma are effective, but face a multitude of challenges limiting efficacy. Nanomedicine presents a viable option to optimize the efficacy of current anti-lymphoma therapies. To achieve most selective drug targeting, optimization of liposome preparations is key. To improve the selective targeting properties of conventional liposomes, cell membrane lipid-extracted nanoliposomes (CLENs) were prepared using lipids extracted from lymphoma target cells. Reported here is results of initial design and development, including physicochemical characterization and in vitro analyses. Methods: The CRL-1593.2 cell line was the chosen cellular model of lymphoma. CRL-1593.2 cells were cultured and expanded In vitro for cellular extraction purposes. The CRL-1593.2 cell lipid extract (LE) was included to prepare CRL-1593.2 CLENs. Conventional lipid ingredients used in preparation of CRL-1593.2-CLENs included DOPC, Cholesterol, and DPPE-Rhodamine (used as a fluorescence indicator) for fluorescence studies using a fluorescence microplate reader. Phase I studies included physicochemical characterization and cellular uptake studies of preparations of CLENs, including 0 to 40 mol% of CRL-1593.2 LE content. In Phase II, the optimal LE content as determined by Phase I was fixed, while cholesterol content varied from 0 to 40 mol%.. For in vitro studies, the control cell lines employed represented other hematological diseases, RPMI 8226 (multiple myeloma), CCRF-CEM (acute lymphoblastic leukemia), and K562-GFP (chronic myeloid leukemia). Results: The optimized composition of CLEN preparation type consisted of DOPC: Cholesterol, lymphoma lipid extract (derived from CRL-1593.2 cells) in the ratio of 93:5:2. The mean particle size was 116 ± 10 nm (n=4) and the mean zeta potential was - 4.5 ± 5 mV (n= 4). For in vitro studies, the inclusion of 2 mol% LE in CRL-1593.2-CLENS demonstrated significant uptake when compared to 0% LE control preparations (P = 0.016). Additionally, the lymphoma cells also had a significantly higher uptake of the CRL-1593.2-CLENs when compared to the other hematological cell lines [(CCL-155; P = 0.0081), (K562-GFP; P = 0.0037) and, (CCRF-CEM; P = 0.0079)]. Conclusions: Early findings collectively suggest that the CRL-1593.2-CLENs is a highly selective drug delivery platform for the targeting of lymphoma cells. Citation Format: Joyce Edlyne Chima Bom, Tien Van Le, Tracy Togba-Bass, Erica Kim, Robert Campbell. Investigating the cellular uptake of liposomal delivery system using cellular models of lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5074.
Abstract 5406: Novel quatramer nano-formulation of dual-targeted PI3-Kδ/HDAC6 inhibitor, HSB-510, suppresses growth of triple negative breast cancer
Authors: Sachchidanand Tiwari, Suiyang Liu, Mohammad Anees, Neha Mehrotra, Ashish Thakur, Gregory Tawa, Gurmit Grewal, Richard M. Stone, Surender M. Kharbanda, Harpal Singh
Journal: Cancer Research (2022)

Abstract Triple negative breast cancer (TNBC) is an aggressive subtype with limited treatment options and a worse clinical outcome as compared with other breast cancer subtypes. Multiple studies have shown that progression of TNBC depends on more than one signalling pathways, suggesting that the therapies with multi-targeted anti-cancer agents will offer improved therapeutic benefit through synergistic effects in inhibiting cancer growth. Dual-targeted inhibitors of phosphoinositide 3-kinase (PI3-K) and histone deacetylase (HDAC) have emerged as promising cancer therapy candidates. However, poor aqueous solubility and bioavailability limited their efficacy in cancer and accordingly, improved delivery systems are needed. The present studies have investigated the encapsulation of PI3-Kδ/HDAC6 dual inhibitor into hybrid block co-polymers (polylactic acid-methoxy polyethylene glycol; polylactic acid-polyethylene glycol-polypropylene glycol-polyethylene glycol-polylactic acid) (HSB-510) as a delivery system to target PI3-Kδ and HDAC6 pathways in TNBC cells. The prepared HSB-510 Quatramer nano-formulation showed an average diameter of 96 ±3 nm, the zeta potential of -17±2 mV, and PDI of ˂0.1 with a slow and sustained release profile of PI3-Kδ/HDAC6 inhibitors in a non-physiological buffer. In vitro studies with HSB-510 have demonstrated substantial growth inhibition of TNBC cell lines, MDA-MB-468, SUM-149 and Ehrlich ascites carcinoma (EAC) as well as downregulation of phospho-AKT, phospho-ERK and c-MYC levels. Importantly, bi-weekly treatment of BALB/c wild-type mice harbouring EAC cells (syngeneic mouse model) with HSB-510 at a dose of 25 mg/kg resulted in significant (76%) tumor growth inhibition (TGI). The treatment with HSB-510 was without any significant effect on the body weights of the mice. These results demonstrate that a novel Quatramer nano-formulation of a novel PI3-Kδ/HDAC6 dual inhibitor (HSB-510) represents an approach for successful targeting of TNBC and potentially other cancer types. Citation Format: Sachchidanand Tiwari, Suiyang Liu, Mohammad Anees, Neha Mehrotra, Ashish Thakur, Gregory Tawa, Gurmit Grewal, Richard M. Stone, Surender M. Kharbanda, Harpal Singh. Novel quatramer nano-formulation of dual-targeted PI3-Kδ/HDAC6 inhibitor, HSB-510, suppresses growth of triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5406.